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Lamivudine And Tenofovir Disoproxil Fumarate

FDA Drug Information • Also known as: Cimduo

Brand Names
Cimduo
Drug Class
Hepatitis B Virus Nucleoside Analog Reverse Transcriptase Inhibitor [EPC], Human Immunodeficiency Virus Nucleoside Analog Reverse Transcriptase Inhibitor [EPC]
Route
ORAL
Dosage Form
TABLET, FILM COATED
Product Type
HUMAN PRESCRIPTION DRUG

⚠ Boxed Warning (Black Box)

WARNING: POST TREATMENT ACUTE EXACERBATIONS OF HEPATITIS B Severe acute exacerbations of hepatitis B have been reported in patients who are co-infected with hepatitis B virus (HBV) and human immunodeficiency virus (HIV-1) and have discontinued lamivudine or tenofovir disoproxil fumarate, components of CIMDUO. Monitor hepatic function closely in these patients and, if appropriate, initiate anti-hepatitis B treatment [see Warnings and Precautions (5.2) ]. WARNING: POST TREATMENT ACUTE EXACERBATIONS OF HEPATITIS B See full prescribing information for complete boxed warning.

  • Severe acute exacerbations of hepatitis B have been reported in patients who are co-infected with HBV and human immunodeficiency virus (HIV-1) and have discontinued lamivudine and tenofovir disoproxil fumarate. Monitor hepatic function closely in these patients and, if appropriate, initiate anti-hepatitis B treatment. ( 5.2 )

    • Description

    11 DESCRIPTION CIMDUO tablets contain lamivudine (also known as 3TC), a synthetic nucleoside analogue with activity against HIV-1 and tenofovir disoproxil fumarate or tenofovir DF, a fumaric acid salt of bis-isopropoxycarbonyloxymethyl ester prodrug of tenofovir. In vivo tenofovir DF is converted to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5’-monophosphate. Tenofovir exhibits activity against HIV-1 reverse transcriptase. The chemical name of lamivudine is (-)-1-[2 R ,5 S ) - 2-Hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine. Lamivudine is the (-)enantiomer of a dideoxy analogue of cytidine. Lamivudine has also been referred to as (-)2′,3′-dideoxy, 3′-thiacytidine. It has a molecular formula of C 8 H 11 N 3 O 3 S and a molecular weight of 229.26 g per mol. It has the following structural formula: Lamivudine is a white to off-white solid with a solubility of approximately 70 mg per mL in water at 20°C. The chemical name of tenofovir DF is 9-[(R)-2-[[Bis[[(isopropoxycarbonyl)oxy]methoxy]phosphinyl]methoxy]propyl]adenine fumarate (1:1). It has a molecular formula of C 19 H 30 N 5 O 10 P

  • C 4 H 4 O 4 and a molecular weight of 635.51. It has the following structural formula: Tenofovir DF is a white to off-white powder with a solubility of 13.4 mg/mL in distilled water at 25°C. It has an octanol/phosphate buffer (pH 6.5) partition coefficient (log p) of 1.25 at 25°C. CIMDUO tablets are for oral administration. Each film-coated tablet contains 300 mg of lamivudine and 300 mg of tenofovir disoproxil fumarate, which is equivalent to 245 mg of tenofovir disoproxil, and the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate and microcrystalline cellulose. The tablet coating contains polyethylene glycol, titanium dioxide, polyvinyl alcohol and talc. Lamivudine Structural Formula Tenofovir Structural Formula

    • What Is Lamivudine And Tenofovir Disoproxil Fumarate Used For?

    1 INDICATIONS AND USAGE CIMDUO ® (lamivudine and tenofovir disoproxil fumarate) is indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adult and pediatric patients weighing at least 35 kg. CIMDUO is a two-drug combination of lamivudine (3TC) and tenofovir disoproxil fumarate (TDF), both nucleo(t)side reverse transcriptase inhibitors and is indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adult and pediatric patients weighing at least 35 kg. ( 1 )

    Dosage and Administration

    2 DOSAGE AND ADMINISTRATION

  • Testing: Prior to initiation and during treatment with CIMDUO, patients should be tested for hepatitis B virus infection, and estimated creatinine clearance, urine glucose, and urine protein should be obtained. ( 2.1 )
  • Recommended dose: One tablet taken orally once daily with or without food. ( 2.2 )
  • Renal Impairment: Not recommended in patients with CrCL less than 50 mL/min or patients with end-stage renal disease requiring hemodialysis. ( 2.3 ) 2.1 Testing Prior to Initiation and During Treatment with CIMDUO Prior to initiation of CIMDUO, test patients for hepatitis B virus infection [see Warnings and Precautions (5.2) ] . It is recommended that serum creatinine, serum phosphorus, estimated creatinine clearance, urine glucose, and urine protein be assessed before initiating CIMDUO and during therapy in all patients as clinically appropriate [see Warnings and Precautions (5.3) ]. 2.2 Recommended Dosage for Adult and Pediatric Patients Weighing at Least 35 kg CIMDUO is a two-drug fixed-dose combination product containing 300 mg of lamivudine (3TC) and 300 mg of tenofovir disoproxil fumarate (TDF). The recommended dosage of CIMDUO in HIV-1-infected adult and pediatric patients weighing at least 35 kg is one tablet taken orally once daily with or without food. 2.3 Not Recommended in Renal Impairment Because CIMDUO is a fixed-dose combination tablet and cannot be dose adjusted, it is not recommended for patients with impaired renal function (creatinine clearance less than 50 mL/min) or patients with end-stage renal disease (ESRD) requiring hemodialysis [see Use in Specific Populations (8.6) ] .

    • Side Effects (Adverse Reactions)

    6 ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling:

  • Lactic Acidosis/Severe Hepatomegaly with Steatosis [see Warnings and Precautions (5.1) ] .
  • Exacerbations of Hepatitis B [see Boxed Warning , Warnings and Precautions (5.2) ] .
  • New Onset or Worsening Renal Impairment [see Warnings and Precautions (5.3) ] .
  • Hepatic Decompensation in Patients Co-infected with HIV-1 and Hepatitis C [see Warnings and Precautions (5.4) ] .
  • Pancreatitis [see Warnings and Precautions (5.5) ] .
  • Decreases in Bone Mineral Density [see Warnings and Precautions (5.6) ] .
  • Immune Reconstitution Syndrome [see Warnings and Precautions (5.7) ] .
  • Fat Redistribution [see Warnings and Precautions (5.8) ] .
  • Most common adverse reactions (> 10% with CIMDUO) are headache, pain, depression, diarrhea, and rash. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, the adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Lamivudine and Tenofovir Disoproxil Fumarate Treatment-Naïve Patients Study 903 - Adverse Reactions The most common adverse reactions seen in a double-blind comparative controlled study in which 600 treatment-naïve subjects received TDF (N = 299) or stavudine (d4T) (N = 301) in combination with 3TC and EFV for 144 weeks were mild to moderate gastrointestinal events and dizziness. Mild adverse reactions (Grade 1) were common with a similar incidence in both arms, and included dizziness, diarrhea, and nausea. Selected moderate to severe adverse reactions are summarized in Table 1. Table 1. Selected Adverse Reactions Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug. (Grades 2-4) Reported in ≥ 5% in Any Treatment Group in Study 903 (0-144 Weeks) TDF + 3TC + EFV d4T + 3TC + EFV N = 299 N = 301 Body as a Whole Headache 14% 17% Pain 13% 12% Fever 8% 7% Abdominal pain 7% 12% Back pain 9% 8% Asthenia 6% 7% Digestive System Diarrhea 11% 13% Nausea 8% 9% Dyspepsia 4% 5% Vomiting 5% 9% Metabolic Disorders Lipodystrophy Lipodystrophy represents a variety of investigator-described adverse events not a protocol-defined syndrome. 1% 8% Musculoskeletal Arthralgia 5% 7% Myalgia 3% 5% Nervous System Depression 11% 10% Insomnia 5% 8% Dizziness 3% 6% Peripheral neuropathy Peripheral neuropathy includes peripheral neuritis and neuropathy. 1% 5% Anxiety 6% 6% Respiratory Pneumonia 5% 5% Skin and Appendages Rash event Rash event includes rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, and pustular rash. 18% 12% Laboratory Abnormalities With the exception of fasting cholesterol and fasting triglyceride elevations that were more common in the stavudine group (40% and 9%) compared with TDF (19% and 1%) respectively, laboratory abnormalities observed in this study occurred with similar frequency in the tenofovir disoproxil fumarate and stavudine treatment arms. A summary of Grade 3 and 4 laboratory abnormalities is provided in Table 2. Table 2. Grade 3/4 Laboratory Abnormalities Reported in ≥ 1% of Tenofovir Disoproxil Fumarate Treated Subjects in Study 903 (0-144 Weeks) TDF + 3TC + EFV d4T + 3TC + EFV N = 299 N = 301 Any ≥ Grade 3 Laboratory Abnormality 36% 42% Fasting Cholesterol (> 240 mg/dL) 19% 40% Creatine Kinase (M: > 990 U/L; F: > 845 U/L) 12% 12% Serum Amylase (> 175 U/L) 9% 8% AST (M: > 180 U/L; F: > 170 U/L) 5% 7% ALT (M: > 215 U/L; F: > 170 U/L) 4% 5% Hematuria (> 100 RBC/HPF) 7% 7% Neutrophils (< 750/mm 3 ) 3% 1% Fasting Triglycerides (> 750 mg/dL) 1% 9% Pancreatitis Pancreatitis, which has been fatal in some cases, has been observed in antiretroviral nucleoside-experienced...

    • Drug Interactions

    7 DRUG INTERACTIONS

  • Atazanavir: Atazanavir should be coadministered with ritonavir when coadministered with CIMDUO. ( 7.2 )
  • HIV-1 Protease Inhibitors: Monitor for evidence of tenofovir toxicity when CIMDUO is coadministrated with atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir. ( 7.2 )
  • Sorbitol: Avoid chronic administration of sorbitol with CIMDUO.( 7.5 ) 7.1 Drugs Affecting Renal Function Since tenofovir is primarily eliminated by the kidneys [see Clinical Pharmacology (12.3) ] , coadministration of CIMDUO with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of tenofovir and/or increase the concentrations of other renally eliminated drugs. Some examples include, but are not limited to cidofovir, acyclovir, valacyclovir, ganciclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs [see Warnings and Precautions (5.3) ] . 7.2 HIV-1 Protease Inhibitors TDF decreases the AUC and C min of atazanavir [see Clinical Pharmacology (12.3) ] . When coadministered with CIMDUO, it is recommended that atazanavir 300 mg is given with ritonavir 100 mg. TDF should not be coadministered with atazanavir without ritonavir. Lopinavir/ritonavir, atazanavir coadministered with ritonavir, and darunavir coadministered with ritonavir have been shown to increase tenofovir concentrations [see Clinical Pharmacology (12.3) ] . Patients receiving CIMDUO concomitantly with lopinavir/ritonavir, atazanavir and ritonavir, or darunavir and ritonavir should be monitored for tenofovir-associated adverse reactions. CIMDUO should be discontinued in patients who develop tenofovir-associated adverse reactions. 7.3 Hepatitis C Antiviral Agents Coadministration of TDF, a component of CIMDUO, and EPCLUSA ® (sofosbuvir/velpatasvir) or HARVONI ® (ledipasvir/sofosbuvir) has been shown to increase tenofovir exposure [see Clinical Pharmacology (12.3) ] . In patients receiving TDF concomitantly with sofosbuvir/velpatasvir, monitor for adverse reactions associated with TDF. In patients receiving CIMDUO concomitantly with ledipasvir/sofosbuvir without an HIV-1 protease inhibitor/ritonavir or an HIV-1 protease inhibitor/cobicistat combination, monitor for adverse reactions associated with tenofovir. In patients receiving CIMDUO concomitantly with ledipasvir/sofosbuvir and an HIV-1 protease inhibitor/ritonavir or an HIV-1 protease inhibitor/cobicistat combination, consider an alternative HCV or antiretroviral therapy, as the safety of increased tenofovir concentrations in this setting has not been established. If coadministration is necessary, monitor for adverse reactions associated with tenofovir. 7.4 Drugs Inhibiting Organic Cation Transporters 3TC, a component of CIMDUO, is predominantly eliminated in the urine by active organic cationic secretion. The possibility of interactions with other drugs administered concurrently should be considered, particularly when their main route...

    • Contraindications

    4 CONTRAINDICATIONS CIMDUO is contraindicated in patients with a previous hypersensitivity reaction to any of the components contained in the formulation.

  • CIMDUO is contraindicated in patients with previous hypersensitivity to any of the components of this product. ( 4 )

    • Pregnancy and Breastfeeding

    8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to CIMDUO during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary Available data from the APR show no difference in the risk of overall major birth defects for 3TC compared to the background rate for major birth defects of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) (see Data ) . 3TC produced embryonic toxicity in rabbits at a dose that produced similar human exposures as the recommended clinical dose. The relevance of animal findings to human pregnancy registry data is not known. There are no adequate and well-controlled studies with TDF in pregnant women. Because animal reproduction studies are not always predictive of human response, TDF should be used during pregnancy only if clearly needed. Human Data Lamivudine Based on prospective reports from the APR of over 11,000 exposures to 3TC during pregnancy resulting in live births (including over 4,300 exposed in the first trimester), there was no difference between 3TC and overall birth defects compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of defects in the first trimester was 3.1% (95% CI: 2.6% to 3.7%). 3TC pharmacokinetics were studied in pregnant women during 2 clinical trials conducted in South Africa. The trials assessed pharmacokinetics in 16 women at 36 weeks gestation using 150 mg 3TC twice daily with zidovudine, 10 women at 38 weeks gestation using 150 mg 3TC twice daily with zidovudine, and 10 women at 38 weeks gestation using 3TC 300 mg twice daily without other antiretrovirals. These trials were not designed or powered to provide efficacy information. 3TC pharmacokinetics in pregnant women were similar to those seen in non-pregnant adults and...

    Overdosage

    10 OVERDOSAGE If overdose occurs the patient must be monitored for evidence of toxicity, and standard supportive treatment applied as necessary. Lamivudine: There is no known specific treatment for overdose with 3TC. If overdose occurs, the patient should be monitored and standard supportive treatment applied as required because a negligible amount of 3TC was removed via (4-hour) hemodialysis, continuous ambulatory peritoneal dialysis, and automated peritoneal dialysis, it is not known if continuous hemodialysis would provide clinical benefit in a 3TC overdose event. Tenofovir Disoproxil Fumarate: Limited clinical experience at doses higher than the therapeutic dose of TDF 300 mg is available. Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. Following a single 300-mg dose of tenofovir disoproxil fumarate, a 4-hour hemodialysis session removed approximately 10% of the administered tenofovir dose.

    How Supplied

    16 HOW SUPPLIED/STORAGE AND HANDLING CIMDUO (lamivudine and tenofovir disoproxil fumarate) tablets 300 mg/300 mg are white to off-white, film-coated, oval tablets debossed with “ M112 ” on one side and plain on the other side. They are supplied as follows: NDC 49502-450-93 cartons containing bottles of 30 tablets with desiccant, induction seal and child-resistant cap NDC 49502-450-77 cartons containing bottles of 90 tablets with desiccant, induction seal and child-resistant cap Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). [See USP Controlled Room Temperature.] Dispense in original container.

    About This Information

    This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

    What are side effects?

    Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

    What are drug interactions?

    Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.